The dual action of poly(ADP-ribose) polymerase -1 (PARP-1) inhibition in HIV-1 infection: HIV-1 LTR inhibition and diminution in Rho GTPase activity.
The dual action of poly(ADP-ribose) polymerase -1 (PARP-1) inhibition in HIV-1 infection: HIV-1 LTR inhibition and diminution in Rho GTPase activity.
复制标题
DOI：
10.3389/fmicb.2015.00878
复制
发表时间：
2015
影响因子：
5.2
通讯作者：
Persidsky Y
中科院分区：
文献类型：
--
作者：
Rom S;Reichenbach NL;Dykstra H;Persidsky Y
由无数细胞因子和病毒编码的反激活因子组成的多因子机制调节HIV-1 （HIV）的转录。由于聚（adp -核糖）聚合酶1 （PARP-1）通过与各种转录因子的相互作用调节许多基因，抑制PARP-1最近被认为是一种强大的抗炎工具。我们提出了一种在体外模型系统中通过抑制PARP-1来减少HIV复制的新策略，利用人原代单核细胞来源的巨噬细胞（MDM）。在感染7天后，抑制PARP-1能够使MDM中的HIV复制减少60-80%。肿瘤坏死因子α (TNFα)和肉豆蔻酸酯13-乙酸磷（PMA）是已知的长末端重复序列（LTR）的触发因子，可以改变病毒的复制。转染LTR报告质粒的MDM过表达导致LTR激活增加4.2倍；PARP抑制使LTR活性降低70%。经PMA或TNFα处理后，LTR活性增加了3倍，PARP抑制降低了LTR活性（85-95%）。在MDM中抑制PARP表现出nf - κ b活性降低90%（已知介导TNFα-和pma诱导的HIV LTR激活）。细胞骨架重排在有效的HIV-1感染中是重要的。PARP失活通过影响Rho GTPase机制减少肌动蛋白细胞骨架重排。这些发现表明，PARP的失活通过抑制LTR激活、NFκB抑制及其对细胞骨架的影响来抑制MDM中的HIV复制。PARP似乎对HIV复制至关重要，其抑制可能为HIV感染的管理提供一种有效的方法。
Multifactorial mechanisms comprising countless cellular factors and virus-encoded transactivators regulate the transcription of HIV-1 (HIV). Since poly(ADP-ribose) polymerase 1 (PARP-1) regulates numerous genes through its interaction with various transcription factors, inhibition of PARP-1 has surfaced recently as a powerful anti-inflammatory tool. We suggest a novel tactic to diminish HIV replication via PARP-1 inhibition in an in vitro model system, exploiting human primary monocyte-derived macrophages (MDM). PARP-1 inhibition was capable to lessen HIV replication in MDM by 60–80% after 7 days infection. Tat, tumor necrosis factor α (TNFα), and phorbol 12-myristate 13-acetate (PMA) are known triggers of the Long Terminal Repeat (LTR), which can switch virus replication. Tat overexpression in MDM transfected with an LTR reporter plasmid resulted in a 4.2-fold increase in LTR activation; PARP inhibition caused 70% reduction of LTR activity. LTR activity, which increased 3-fold after PMA or TNFα treatment, was reduced by PARP inhibition (by 85–95%). PARP inhibition in MDM exhibited 90% diminution in NFκB activity (known to mediate TNFα- and PMA-induced HIV LTR activation). Cytoskeleton rearrangements are important in effective HIV-1 infection. PARP inactivation reduced actin cytoskeleton rearrangements by affecting Rho GTPase machinery. These discoveries suggest that inactivation of PARP suppresses HIV replication in MDM by via attenuation of LTR activation, NFκB suppression and its effects on the cytoskeleton. PARP appears to be essential for HIV replication and its inhibition may provide an effective approach to management of HIV infection.